Supercomplex Explained

Modern biological research has revealed strong evidence that the enzymes of the mitochondrial respiratory chain assemble into larger, supramolecular structures called supercomplexes, instead of the traditional fluid model of discrete enzymes dispersed in the inner mitochondrial membrane. These supercomplexes are functionally active and necessary for forming stable respiratory complexes.[1]

One supercomplex of complex I, III, and IV make up a unit known as a respirasome. Respirasomes have been found in a variety of species and tissues, including rat brain,[2] liver, kidney, skeletal muscle,[3] heart, bovine heart,[4] human skin fibroblasts,[5] fungi,[6] plants,[7] [8] and C. elegans.[9]

History

In 1955, biologists Britton Chance and G. R. Williams were the first to propose the idea that respiratory enzymes assemble into larger complexes,[10] although the fluid state model remained the standard. However, as early as 1985, researchers had begun isolating complex III/complex IV supercomplexes from bacteria[11] [12] [13] and yeast.[14] [15] Finally, in 2000 Hermann Schägger and Kathy Pfeiffer used Blue Native PAGE to isolate bovine mitochondrial membrane proteins, showing Complex I, III, and IV arranged in supercomplexes.[16]

Composition and formation

The most common supercomplexes observed are Complex I/III, Complex I/III/IV, and Complex III/IV. Most of Complex II is found in a free-floating form in both plant and animal mitochondria. Complex V can be found co-migrating as a dimer with other supercomplexes, but scarcely as part of the supercomplex unit.

Supercomplex assembly appears to be dynamic and respiratory enzymes are able to alternate between participating in large respirasomes and existing in a free state. It is not known what triggers changes in complex assembly, but research has revealed that the formation of supercomplexes is heavily dependent upon the lipid composition of the mitochondrial membrane, and in particular requires the presence of cardiolipin, a unique mitochondrial lipid.[17] In yeast mitochondria lacking cardiolipin, the number of enzymes forming respiratory supercomplexes was significantly reduced.[18] According to Wenz et al. (2009), cardiolipin stabilizes the supercomplex formation by neutralizing the charges of lysine residues in the interaction domain of Complex III with Complex IV.[19] In 2012, Bazan et al. was able to reconstitute trimer and tetramer Complex III/IV supercomplexes from purified complexes isolated from Saccharomyces cerevisiae and exogenous cardiolipin liposomes.[20]

Another hypothesis for respirasome formation is that membrane potential may initiate changes in the electrostatic/hydrophobic interactions mediating the assembly/disassembly of supercomplexes.[21]

Functional significance

The functional significance of respirasomes is not entirely clear but more recent research is beginning to shed some light on their purpose. It has been hypothesized that the organization of respiratory enzymes into supercomplexes reduces oxidative damage and increases metabolism efficiency. Schäfer et al. (2006) demonstrated that supercomplexes comprising Complex IV had higher activities in Complex I and III, indicating that the presence of Complex IV modifies the conformation of the other complexes to enhance catalytic activity.[22] Evidence has also been accumulated to show that the presence of respirasomes is necessary for the stability and function of Complex I. In 2013, Lapuente-Brun et al. demonstrated that supercomplex assembly is "dynamic and organizes electron flux to optimize the use of available substrates."[23]

Notes and References

  1. Vartak. Rasika. Porras. Christina Ann-Marie. Bai. Yidong. Respiratory supercomplexes: structure, function and assembly. Protein & Cell. 4. 8. 2013. 582–590. 1674-800X. 10.1007/s13238-013-3032-y. 23828195. 4708086.
  2. Reifschneider. Nicole H.. Goto. Sataro. Nakamoto. Hideko. Takahashi. Ryoya. Sugawa. Michiru. Dencher. Norbert A.. Krause. Frank. Defining the Mitochondrial Proteomes from Five Rat Organs in a Physiologically Significant Context Using 2D Blue-Native/SDS-PAGE. Journal of Proteome Research. 5. 5. 2006. 1117–1132. 1535-3893. 10.1021/pr0504440. 16674101.
  3. Lombardi. A.. Silvestri. E.. Cioffi. F.. Senese. R.. Lanni. A.. Goglia. F.. de Lange. P.. Moreno. M.. Defining the transcriptomic and proteomic profiles of rat ageing skeletal muscle by the use of a cDNA array, 2D- and Blue native-PAGE approach. Journal of Proteomics. 72. 4. 2009. 708–721. 1874-3919. 10.1016/j.jprot.2009.02.007. 19268720.
  4. Schäfer. Eva. Dencher. Norbert A.. Vonck. Janet. Parcej. David N.. Three-Dimensional Structure of the Respiratory Chain Supercomplex I1III2IV1from Bovine Heart Mitochondria†,‡. Biochemistry. 46. 44. 2007. 12579–12585. 0006-2960. 10.1021/bi700983h. 17927210.
  5. Rodríguez-Hernández. Ángeles. Cordero. Mario D.. Salviati. Leonardo. Artuch. Rafael. Pineda. Mercé. Briones. Paz. Gómez Izquierdo. Lourdes. Cotán. David. Navas. Plácido. Sánchez-Alcázar. José A.. Coenzyme Q deficiency triggers mitochondria degradation by mitophagy. Autophagy. 5. 1. 2009. 19–33. 1554-8627. 10.4161/auto.5.1.7174. 19115482. 10261/40287. free. free.
  6. Krause. F.. OXPHOS Supercomplexes: Respiration and Life-Span Control in the Aging Model Podospora anserina. Annals of the New York Academy of Sciences. 1067. 1. 2006. 106–115. 0077-8923. 10.1196/annals.1354.013. 16803975. 2006NYASA1067..106K . 9939670 .
  7. Eubel. Holger. Heinemeyer. Jesco. Sunderhaus. Stephanie. Braun. Hans-Peter. Respiratory chain supercomplexes in plant mitochondria. Plant Physiology and Biochemistry. 42. 12. 2004. 937–942. 0981-9428. 10.1016/j.plaphy.2004.09.010. 15707832.
  8. Sunderhaus. Stephanie. Klodmann. Jennifer. Lenz. Christof. Braun. Hans-Peter. Supramolecular structure of the OXPHOS system in highly thermogenic tissue of Arum maculatum. Plant Physiology and Biochemistry. 48. 4. 2010. 265–272. 0981-9428. 10.1016/j.plaphy.2010.01.010. 20144873.
  9. Suthammarak. Wichit. Somerlot. Benjamin H.. Opheim. Elyce. Sedensky. Margaret. Morgan. Philip G.. Novel interactions between mitochondrial superoxide dismutases and the electron transport chain. Aging Cell. 12. 6. 2013. 1132–1140. 1474-9718. 10.1111/acel.12144. 23895727. 3838459.
  10. Chance. Britton. Williams. G. R.. A Method for the Localization of Sites for Oxidative Phosphorylation. Nature. 176. 4475. 1955. 250–254. 0028-0836. 10.1038/176250a0. 13244669. 1955Natur.176..250C . 4184316 .
  11. E. A. Berry & B. L. Trumpower . Isolation of ubiquinol oxidase from Paracoccus denitrificans and resolution into cytochrome bc1 and cytochrome c-aa3 complexes . . 260 . 4 . 2458–2467 . February 1985 . 10.1016/S0021-9258(18)89576-X . 2982819. free .
  12. T. Iwasaki, K. Matsuura & T. Oshima . Resolution of the aerobic respiratory system of the thermoacidophilic archaeon, Sulfolobus sp. strain 7. I. The archaeal terminal oxidase supercomplex is a functional fusion of respiratory complexes III and IV with no c-type cytochromes . . 270 . 52 . 30881–30892 . December 1995 . 8537342 . 10.1074/jbc.270.52.30881. free .
  13. N. Sone, M. Sekimachi & E. Kutoh . Identification and properties of a quinol oxidase super-complex composed of a bc1 complex and cytochrome oxidase in the thermophilic bacterium PS3 . . 262 . 32 . 15386–15391 . November 1987 . 10.1016/S0021-9258(18)47736-8 . 2824457. free .
  14. H. Boumans, L. A. Grivell & J. A. Berden . The respiratory chain in yeast behaves as a single functional unit . . 273 . 9 . 4872–4877 . February 1998 . 9478928 . 10.1074/jbc.273.9.4872. free .
  15. C. Bruel, R. Brasseur & B. L. Trumpower . Subunit 8 of the Saccharomyces cerevisiae cytochrome bc1 complex interacts with succinate-ubiquinone reductase complex . Journal of Bioenergetics and Biomembranes . 28 . 1 . 59–68 . February 1996 . 8786239 . 10.1007/bf02109904. 23909319 .
  16. H. Schagger & K. Pfeiffer . Supercomplexes in the respiratory chains of yeast and mammalian mitochondria . . 19 . 8 . 1777–1783 . April 2000 . 10.1093/emboj/19.8.1777 . 10775262 . 302020.
  17. Zhang. M.. Gluing the Respiratory Chain Together. CARDIOLIPIN IS REQUIRED FOR SUPERCOMPLEX FORMATION IN THE INNER MITOCHONDRIAL MEMBRANE. Journal of Biological Chemistry. 277. 46. 2002. 43553–43556. 0021-9258. 10.1074/jbc.C200551200. 12364341. free.
  18. Zhang. M.. Cardiolipin Is Essential for Organization of Complexes III and IV into a Supercomplex in Intact Yeast Mitochondria. Journal of Biological Chemistry. 280. 33. 2005. 29403–29408. 0021-9258. 10.1074/jbc.M504955200. 15972817. 4113954. free .
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  20. Bazan. S.. Mileykovskaya. E.. Mallampalli. V. K. P. S.. Heacock. P.. Sparagna. G. C.. Dowhan. W.. Cardiolipin-dependent Reconstitution of Respiratory Supercomplexes from Purified Saccharomyces cerevisiae Complexes III and IV. Journal of Biological Chemistry. 288. 1. 2012. 401–411. 0021-9258. 10.1074/jbc.M112.425876. 23172229. 3537037. free .
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